oxLDL and hyperlipidemia caused decreased platelet sensitivity to cGMP through NOX2. (A) Human platelets were stained with DiOC₆ (1 µmol/L) for 10 minutes at 37°C, reconstituted with RBCs, treated with either nLDL or oxLDL for 15 minutes, and then perfused through fibrinogen (1 mg/mL) or bovine serum albumin (BSA)-coated capillary tubes for 2 minutes at a shear rate of 1000 s⁻¹. (i) Shown are images representative of 3 independent experiments with separate blood donors. Scale bar, 20 µm. (ii) Data are presented as surface area coverage (%) (n = 3). **P < .01, fibrinogen compared with cGMP, and oxLDL in the presence and absence of inhibitors. (B) Blood from WT and ApoE^−/− mice were stimulated with ADP (10 µM) in the presence and absence of 8pCPT-cGMP (50 µmol/L) and platelet fibrinogen binding measured by flow cytometry. (i) Data are presented as % inhibition of fibrinogen (Fgn) binding and are expressed as mean ± SEM taken from 9 individual mice for each group. *P < .05. Representative fluorescence-activated cell sorter histograms of fibrinogen binding for WT (ii), sc-gp91ds-tat (iii), and gp91ds-tat (iv). Each histogram shows fibrinogen binding at basal (red line), ADP (10 µM) (green line), and 8pCPT-cGMP (50 µmol/L)/ADP (blue line). (C) Summary of the proposed signaling pathway downstream of CD36 through which oxLDL activates gp91^phox/NOX2 and suppresses PKG signaling. sGC, soluble guanylyl cyclase; NS, not significant.